It has therefore been argued that the apparent continuing failure to develop fundamentally new and different analgesic drugs contributes significantly to the unmet needs in chronic pain
Trang 1279 MTX = methotrexate; NSAID = non-steroidal anti-inflammatory drug; OA = osteoarthritis; RA = rheumatoid arthritis.
Available online http://arthritis-research.com/content/6/6/279
Despite the availability of opium and willow-bark derivatives
for centuries, chronic pain remains an important unmet
public health need Although definitive epidemiologic data
are lacking, millions of Americans [1] live with serious
(malignant and non-malignant) chronic pain; this pain
subsequently affects almost every aspect of their lives In
fact, a recent study suggests that chronic pain has a
greater impact (about US$100 billion annually) on the US
economy in health insurance, lost wages, and reduced
productivity than any other chronic condition including
heart disease, hypertension, and diabetes [2] Unmet
needs for analgesia are also recognized by the US
Congress, which has declared 2000–10 to be ‘The
decade of pain management and research’ Although the
recognition of pain as the ‘fifth vital sign’, continuing
improvements in professional pain education, and the
development of pain and palliative care services hold
promise for improved pain therapy, these efforts are
ultimately limited by the safety and efficacy of opioids,
non-steroidal anti-inflammatory drugs (NSAIDs) and all their
variations and formulations It has therefore been argued
that the apparent continuing failure to develop
fundamentally new and different analgesic drugs
contributes significantly to the unmet needs in chronic pain management [3] This further suggests that there is a need for new strategies and new thinking regarding therapeutic targets for treating pain, both acute and chronic
To rheumatologists, the statement that there are unmet clinical needs in chronic pain is probably not too surprising because they deal routinely with chronic pain in their patients with osteoarthritis (OA), a leading cause of chronic pain and disability in the USA estimated to affect nearly 21 million Americans [4] Treating the chronic pain associated with OA alone costs millions of dollars in direct analgesic drug costs, as well as those costs necessary to deal with the inevitable adverse events (namely gastrointestinal bleeds) that these drugs also bring to the therapeutic table Similarly, pain associated with other arthritic diseases such as rheumatoid arthritis (RA), which affects an estimated 1% of US adults, is another example
of other causes of chronic pain in rheumatic diseases Possibly even more familiar to rheumatologists today is the increasingly recognized condition called fibromyalgia that currently represents a substantial unmet need and clinical challenge for pain therapy In fact, probably all
rheumato-Commentary
What can chronic arthritis pain teach about developing new
analgesic drugs?
James Witter1and Raymond A Dionne2
1 Center for Drug Evaluation & Research (CDER), FDA, Rockville, Maryland, USA
2 National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA
Corresponding author: Raymond Dionne, raymond.dionne@nih.gov
Published: 15 October 2004
Arthritis Res Ther 2004, 6:279-281 (DOI 10.1186/ar1450)
© 2004 BioMed Central Ltd
Abstract
Chronic pain remains an important public health need with greater impact on the US economy than
most other chronic conditions Current pain management is largely limited to opioids and non-steroidal
anti-inflammatory drugs, indicating a gap in the translation of new knowledge to the development of
improved pain treatments Strategies suggested include the re-evaluation of current drug screening
methods, a recognition that molecular-genetic events occurring acutely contribute to the development
of pain chronicity, the validation of analgesic targets in the intended patient population, consideration
of the unique genetic profile that varies between individuals, and the introduction of individual response
measures to improve the capture of outcomes in clinical trials
Keywords: analgesics, chronic pain, drug development, individual responses, pain mechanisms
Trang 2Arthritis Research & Therapy Vol 6 No 6 Witter and Dionne
logic diseases can evoke pain at some point that is often
poorly managed Therefore, patients who frequent a
rheumatologist in the clinic represent a substantial portion
of the total US burden of chronic pain and also arguably
present the spectrum of mechanisms that cause such pain
Despite the sequencing of the human genome, the cloning
of animals and the advent of clinically useful biological
agents to treat a wide variety of diseases (especially
rheumatic diseases), few truly new and widely effective
molecular entities designed to treat pain mechanisms have
entered the analgesic clinic in the past 10–20 years Why,
then, is there such a gap in the translation of new knowledge
and technologies into different and better treatments for one
of the oldest medical problems known to humans?
It is likely that the potential of genomics and proteomics
will permit a better description of the molecular-genetic
basis of acute and chronic inflammation These new tools
and thinking will also probably lead to a deeper
understanding of the plasticity in the nervous system that
is argued to be an important pathway to chronic pain that
no longer depends on obvious peripheral causes It is
therefore likely that this new knowledge will lead to new
targets for analgesia and new chemical entities entering
the drug development pipeline of the future However,
existing clinical trial settings have the apparent limitation of
only identifying drugs with mechanisms of action similar to
already approved drugs, while screening out analgesics
with completely new mechanisms of action, as these
clinical models have usually been validated by
demon-strating opioid or NSAID activity This circular process
therefore may fail to detect drugs acting through
non-opioid or non-NSAID mechanisms because these
investi-gational analgesics might never advance beyond the initial
proof-of-concept studies The high cost of drug
development, now estimated at $800 million per new
chemical entity [5], may further act as a deterrent to
developing truly novel analgesics, because a failure would
be too costly
A recent workshop organized jointly by the National
Institutes of Health and the US Food and Drug
Administration [3] identified several methodologic issues
that act as barriers toward the development of novel
analgesic drugs It was noted, for example, that most pain
research conducted in the past 150 years has studied
transient pain that does not result in tissue damage
sufficient to have much relevance to clinical medicine as a
model for chronic disease The artificial temporal
differentiation between acute (days to weeks) and chronic
(months) pain may also be problematic because key
pathophysiologic processes may diverge early in the
development of pain chronicity Chronic pain studies
based on enrolling patients who have had pain for months
might miss critical points for evaluating an intervention
aimed at preventing or pre-empting the development of the chronic disorder and subsequent irreversible changes This situation may be especially true for the contribution of peripheral and central sensitization to the transition from acute injury to chronic pain
Conversely, traditional animal and clinical models employed to screen for analgesics might not be useful for studying the transition from acute injury to chronic pain if the critical events occur days after the injury when acute pain is usually resolving symptomatically This limitation is even more important if these same pain models are not able to identify analgesics that have a fundamentally different mechanism of action from that of traditional NSAIDs or opioid-type drugs This discrepancy is illustrated by the promise suggested for neurokinin-1 antagonists by animal-based studies and their failure to demonstrate analgesic activity in human clinical conditions [6] This disconnect may also illustrate that currently available non-clinical animal models are not good surrogates for the clinical needs of chronic pain Therefore, if non-clinical models that are sensitive to mechanisms other than anti-inflammatory effects cannot readily be developed, other alternatives in the clinical setting need to be explored
A shift in the strategies used for analgesic drug development is called for by Woolf and colleagues [7] They argue that understanding analgesic mechanisms provides an opportunity to move forward by assessing the effects of investigational analgesics on the mechanisms involved rather than the empirical method that has driven analgesic development in the past The symptoms that comprise the pain experience are the result of specific and identifiable changes in the nervous system Analgesics, Woolf argues, do not have intrinsic pain-relieving actions; rather, they produce their effects because they interfere with the mechanisms that produce the pain Analgesia will not occur if the particular mechanism that a drug interacts with is not present in the patient Conversely, if a patient has a pathophysiologic process that is driving their pain, that mechanism should be the target of action of the analgesic This extends to the clinical differences between acute and chronic pain; they are not distinct states of the nervous system Acute pain refers to pain at certain times after initiating events that may be transient; chronic pain refers to the persistence of the mechanisms activated by the tissue injury The way to move forward clinically is to measure multiple signs and symptoms, not just global measures such as patient report of pain, and to validate hypotheses about the mechanisms that convert a short-lasting pain into a pain that persists and becomes intractable rather than returning to baseline
Pharmacogenomics is another possible strategy for enhancing analgesic drug development and pain therapy It
Trang 3rests on the ability to relate the responses of an individual
to a drug regimen to some aspect of their genetic
composition If demonstrated in a sufficient number of
individuals, it might be possible to derive a causal
relationship between specific genetic polymorphisms and
therapeutic response If one’s genetic profile influences
one’s molecular pathways for pain and response to an
analgesic in terms of efficacy or safety, these important
factors may revolve around the unique individual
Properly constructed individual response measures hold
the potential to improve the capture of clinical outcomes in
clinical trials; more so than approaching the same problem
from a group or means perspective (RA Dionne, L
Bartoshuk, J Mogil and J Witter, unpublished work)
Validating the role of an individual responder approach for
clinical analgesic trials will better capture clinically
important outcomes in clinical trials, possibly leading to the
identification of subgroups of patients whose underlying
molecular-genetic pain mechanism provides a favorable
therapeutic ratio for an analgesic drug
Therefore, in thinking about the transition from acute pain
after tissue injury to chronic pain sustained in the absence
of damage, one can then ask the following types of
question: How much of chronic pain is caused by
mechanisms that are initiated by acute pain processes in
the periphery, for example inflammation; by reactive
processes in the central nervous system, for example
sensitization due to the release of excitatory amino acids;
and by the continuing disease process, for example RA or
OA? Should drug selection for these distinct processes
vary to target the acute inflammatory response, the
transition to chronicity, or the underlying disease process
to minimize continued destructive changes despite
successful symptom management? Should pivotal clinical
trials for screening and confirming investigational drugs
continue to be based on clinical models that have been
validated with the use of existing drug classes (NSAIDs,
opioids), or will scientific advances translate more
successfully into improved pain therapy by the
development of new approaches to clinical evaluation of
putative analgesic drugs?
Both the drug methotrexate (MTX) and the biologic agent
etanercept are examples of therapies widely employed to
treat rheumatoid arthritis The evidence to support such
use comes from clinical trials that have used the American
College of Rheumatology (ACR) 20 responder analysis as
the endpoint Pain relief is the primary goal of any therapy
in RA, and the ACR 20 employs pain (100 mm visual
analog scale) as one of its endpoints Because the
response to MTX generally takes days to weeks to
become apparent, it is not surprising that there is no
information available in the literature to suggest that MTX
would be useful to treat acute pain This would therefore
suggest that whatever mechanisms underlie how MTX improves pain in RA are different from those that cause pain in an acute situation In contrast, the pain relief associated with the use of etanercept has been described
as rapid and dramatic, suggesting that the tumor necrosis factor pathway has an equally important role in chronic pain and the other processes associated with chronic inflammation It is noteworthy that neither MTX nor etanercept has found use in the chronic pain associated with fibromyalgia It is therefore unknown how these two arthritic therapies differ in their ability to interfere with the underlying disease processes that contribute to nociceptive processes versus the symptom complex called pain as experienced in the somatosensory cortex Furthermore, it is likely that neither agent would have survived for long in a traditional analgesic development program with a ‘pivotal’ clinical trial in an acute anti-inflammatory model such as oral surgery or bunion surgery
So perhaps a reconsideration of acute versus chronic pain, and acute versus chronic inflammation, might be useful as we move forward in this ‘Decade of pain management and research’ A better understanding of the relationships that exist mechanistically in acute versus chronic pain might allow the development of new therapies that will optimize the treatment of pain Acute pain that is treated from an understanding of both a mechanistic and clinical perspective may lower the probability that such acute pain might ultimately contribute
to chronic pain Chronic pain that is treated from an understanding of its mechanistic and clinical perspectives might then be pain that is ultimately cured
Competing interests
The author(s) declare that they have no competing interests
Acknowledgements
The views expressed are those of the authors No official support or endorsement by the US Food and Drug Administration or the National Institutes of Health is provided or should be inferred.
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Available online http://arthritis-research.com/content/6/6/279